rs781287267

Variant names:

• chr1-27332092-A-G
• rs781287267
• NM_032125.3:c.302A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032125.3(TMEM222):​c.302A>G​(p.Lys101Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TMEM222 NM_032125.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60
• Publications: 0 publications found

Genes affected

TMEM222 (HGNC:25363): (transmembrane protein 222) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM222 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with motor and speech delay and behavioral abnormalities

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, LiferaOmics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000304055 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21622556).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM222	NM_032125.3	MANE Select	c.302A>G	p.Lys101Arg	missense	Exon 3 of 6	NP_115501.2	Q9H0R3-1
	TMEM222	NR_037576.2		n.408A>G		non_coding_transcript_exon	Exon 4 of 7
	TMEM222	NR_037577.2		n.255A>G		non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM222	ENST00000374076.9	TSL:1 MANE Select	c.302A>G	p.Lys101Arg	missense	Exon 3 of 6	ENSP00000363189.4	Q9H0R3-1
	TMEM222	ENST00000611517.4	TSL:1	c.302A>G	p.Lys101Arg	missense	Exon 3 of 6	ENSP00000483276.1	Q9H0R3-1
	TMEM222	ENST00000608611.5	TSL:1	c.203A>G	p.Lys68Arg	missense	Exon 3 of 6	ENSP00000476439.1	Q8TDQ4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251462 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.27	N
PhyloP100		3.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.23
Sift	Benign	0.51	T
Sift4G	Benign	0.57	T
Polyphen		0.091	B
Vest4		0.30
MutPred		0.38		Loss of methylation at K101 (P = 0.0226)
MVP		0.15
MPC		0.29
ClinPred		0.22	T
GERP RS		5.8
Varity_R		0.062
gMVP		0.45
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781287267; hg19: chr1-27658583;